Neurokinin receptors such as the NK.sub.1 and the NK.sub.2 receptors are found in the central nervous system, the circulatory system, and the peripheral tissues of mammals, and are involved in a variety of biological processes. Antagonists of the neurokinin receptors are, therefore, expected to be useful in the treatment or prevention of various mammalian diseases such as, for example, pulmonary disorders such as asthma, cough, bronchospasm, chronic obstructive pulmonary diseases, and airway hyperactivity; skin disorders and itch, for example, atopic dermatitis, and cutaneous wheal and flare; neurogenic inflammatory diseases such as, arthritis, migraine, nociception; CNS diseases such as anxiety, emesis, Parkinson's disease, movement disorders and psychosis; convulsive disorders, renal disorders, urinary incontinence, ocular inflammation,, inflammatory pain, and eating disorders such as food intake inhibition; allergic rhinitis, neurodegenerative disorders, psoriasis, Huntington's disease, depression and various disorders such as Crohn's disease. NK.sub.1 receptors have been reported to be involved in microvascular leakage and mucus secretion, and NK.sub.2 receptors have been associated with smooth muscle contraction, making NK.sub.1 and NK.sub.2 receptor antagonists especially useful in the treatment and prevention of asthma. NK.sub.1 and NK.sub.2 receptor antagonists have been reported such as, for example, in U.S. Pat. Nos. 5,798,359; 5,795,894; 5,789,422; 5,783,579; 5,719,156; 5,696,267; 5,691,362; 5,688,960; 5,654,316; and in "Recent Advances in eurokinin Receptor Antagonists", by C. J. Ohnmacht Jr., et al, Annual Reports in Medicinal Chemistry, A. M. Doherty Ed., 33, 71-80 (1998).
The usefulness of antihistamines that act by blocking the action of histamine on the H.sub.1 receptor for treatment and prevention of allergic rhinitis and related disorders is well known. A discussion is provided by, for example, R. Aslanian et al, Exp. Opin. Ther. Patents, 7(3), 201-207 (1997) as well as in references cited therein.
The discovery of the H.sub.3 receptor is a fairly recent phenomenon. The H.sub.3 receptor is most abundantly distributed in the CNS, and in lesser amounts in peripheral tissues. The H.sub.3 receptor is considered an important general neuroregulatory mechanism for various physiological processes, not only in the CNS but in peripheral tissues as well. A discussion of the H.sub.3 receptor and antagonists therefor can be found in J. G. Phillips et al, Annual Reports in Medicinal Chemistry, J. Bristol, ed., 33, 31-40 (1998).
Compounds that antagonize both the NK.sub.1 and H.sub.1 receptors are disclosed, for example, in WO 96-06094 (Marion Merrell Dow, 1996). Dual antagonists of the H.sub.1 and H.sub.3 receptors are discussed, for example, in pending U.S. patent application, Ser. No. 08/909,319, filed Aug. 14, 1997. Pending U.S. patent application, Ser. No. 60/068,638, filed Dec. 23, 1997, discloses compositions comprising leukotriene antagonists and H.sub.1 receptors.
It would be highly desirable to enhance the efficacy of the neurokinin antagonists to improve their overall efficacy.